Even when a physiologically peptide which is able to be applied as a drug is present, some of the peptide has a short half-life in plasma and, in its application for therapeutic purpose, it is necessary to attempt the achievement by means of the continuous administration by intravenous or subcutaneous means or by administration of a DDS preparation of a sustained release type. Therefore, much time and cost for a long period of time are necessary for actual application.
For example, as an example where the half-life in plasma of the physiologically active peptide is extended and development as a drug is conducted, there is a case of glucagons-like peptide-1 (Non-Patent Document 1). In clinical studies for clarifying the action of the physiologically active peptide, a sustained release intravenous administration has been much used (Non-Patent Document 2) and, for the treatment of type 2 diabetes mellitus, a peptide where half-like is extended whereby a bolus subcutaneous administration is possible has been created. As such, in order to develop as an actual treating agent, there is a case where development of derivatives where a half-life is extended is necessary and, in such a case, physiologically active peptide derivatives are chemically synthesized or, even in the case of different type of natural peptide, that having a long half-life has been developed (Non-Patent Documents 3 to 5).
When a physiologically active peptide having a short half-life is to be applied as a drug, there is an attempt where it is bonded to a protein having a long half-life so that the half-life of the physiologically active peptide is made near the half-life of the protein. For example, an attempt such as that the object physiologically active protein and the protein are bonded via a spacer having a bonding group to a serum albumin has been in a testing stage (Non-Patent Document 6).
Accordingly, for subjecting the physiologically active peptide having a short half-life to a practical use, it has been expected that the pharmacokinetics in vivo is improved by adding a substance which is able to extent the half-life whereby the physiologically active peptide which was unable to exhibit a therapeutic effect by the prior art is applied to a medical purpose.
Attempts where the physiologically active peptide having a short half-like is modified so as to apply it as a drug have been widely carried out already. It has been attempted to stabilize the peptide, to give a sustaining property by an improvement in the preparation, etc. and examples where the practical implementation was successful have been known as well.
On the other hand, ghrelin is a hormone which was found in the stomach in 1999, has an amino acid sequence comprising 28 residues and is a peptide having a very unusual chemical structure where the third amino acid from the amino terminal of the sequence is acylated with fatty acid (Non-Patent Document 6 and Patent Document 1). Ghrelin is an endogenous brain- and digestive tract-hormone (Non-Patent Document 7) which acts on a growth hormone secretagogue-receptor 1a (GHS-R1a) (Non-Patent Document 7) to promote the secretion of growth hormone (GH) from pituitary gland.
Further, ghrelin was firstly isolated and purified from rats as an endogenous GHS for GHS-R1a. Moreover, ghrelin having the similar primary structure has been also isolated from vertebrate animals other than rat such as human, mouse, swine, domestic fowl, eel, cattle, horse, sheep, frog, rainbow trout or dog and the amino acid sequence thereof has been known already (Patent Document 1 and Non-Patent Document 8). All of the above ghrelin is a peptide where a side-chain hydroxyl group of the serine residue or threonine residue at 3-position is acylated by fatty acid such as octanoic acid or decanoic acid and, with regard to the physiologically active peptide having such a hydrophobically modified structure, there has been no example of being isolated from living body except ghrelin.
In the recent studies, it has been clarified that ghrelin promotes the appetite, that a subcutaneous administration of ghrelin increases body weight and body fat (Non-Patent Documents 9 to 11) and that an action such as improving the cardiac function is available (Non-Patent Documents 12 to 14). Further, ghrelin has a promoting action for GH secretion and a promoting action for appetite and it has been expected that an action where fat is burned via the action of GH so as to convert into energy or an effect where anabolic action of GH is expressed so as to potentiate the muscle is able to be more effectively brought out by promotion of appetite (Non-Patent Document 15).
However, the current status is that, although the active center of ghrelin is shown to be an N-terminal moiety having an acyl group (Patent Document 1), there are still ambiguous points for the physiological significance of the C terminal moiety.